It is now clear that under certain experimental conditions mature central neurons can regenerate after spinal cord injury. Interventions that alter the environment at the injury site and others that increase the intrinsic neuronal capacity for re-growth both contribute to the regeneration. This axonal regrowth also contributes to recovery of both skilled forelimb function and locomotion. We hypothesize that remodeling of central projections after injury in the CNS is not restricted to those neurons damaged directly. Little is known about the extent of anatomical reorganization that occurs in the injured CNS after spinal cord injury. Still less is understood about how this reorganization is influenced by alterations in the level of activity after injury. We hypothesize that supraspinal neurons rostral to the injury and changes in their input under different experimental conditions play a major role in recovery of function after spinal cord injury. We also hypothesize that specific activity (rehabilitation) increases both the extent of anatomical plasticity and the amount of functional recovery that occurs. The experiments proposed use high cervical spinal cord over hemi-section, transplants and neurotrophic factors to examine the nature and extent of this supraspinal reorganization and its contribution to recovery of locomotion and skilled forelimb movement. We will use anterograde and retrograde neuroanatomical tracing and quantitative morphometrics to identify the alterations in neuronal circuitry above the spinal cord injury. As models we will examine reorganization in cortical and cerebellar afferents to the red nucleus, descending and segmental input to propriospinal neurons and sensory afferents to the dorsal column nuclei and sensorimotor cortex. We also hypothesize that both the anatomical reorganization and behavioral recovery can be modified by experience and activity after injury. We will use quantitative analysis of motor function, and neuroanatomical tracing and quantitative morphometrics to determine the extent to which changes in activity alter the anatomical reorganization and alter functional recovery. Taken together, these studies will increase our understanding of the plasticity that occurs in the supraspinal circuitry after spinal cord injury and regeneration. This circuitry will play a critical role in recovery of function after spinal cord injury. A better understanding of the changes that take place within the injured CNS and how they are regulated will be important in understanding how rehabilitation strategies can increase neuroplasticity and functional recovery in humans after spinal cord injury.